Targeted therapy using venetoclax with bortezomib/dexamethasone: preliminary data indicates positive results for RRMM

On 28^th August, results from a study assessing the combination of venetoclax with bortezomib and dexamethasone, in patients with Relapsed and/or Refractory Multiple Myeloma (RRMM), was published in Blood. Anti-apoptotic proteins from the BCL-2 family, including MCL-1, are known to promote MM cell survival and are particularly overexpressed in myeloma cells. Venetoclax is a strong inhibitor of BCL-2 proteins with the ability to restart the apoptotic pathway and cause cell death. Bortezomib inhibits MCL-1 with the potential to provide synergy with venetoclax, whilst dexamethasone increases cell sensitivity to venetoclax. The phase Ib study led by Philippe Moreau, from the Hematology Department, University of Nantes, and Simon J. Harrison from the Peter MacCallum Cancer Centre, University of Melbourne, Australia, and colleagues, tested the combination of these agents in a phase Ib trial for efficacy and safety.

Study Design:

• Open label, multi-center, phase Ib study (November 2012 – May 2016)
• Patients (pts) enrolled in the study = 66; median age = 64
• Venetoclax was administered orally, once daily
• Patients were refractory to previous treatments: lenalidomide (53%), bortezomib (39%) and prior stem cell transplant (59%)
• Primary objectives were to assess the safety and efficacy of venetoclax with bortezomib and dexamethasone and determine a maximum tolerated dose
• Secondary objectives were to determine Overall Response Rate (ORR), Time to Disease Progression (TTP) and Duration of Overall Response (DOR).

Key Findings:

• ORR = 67%
• Very Good Partial Response or better ≥VGPR = 42%
• Median TTP = 9.5 months (95% CI: 5.7, 10.4)
• Median DOR = 9.7 months (95% CI: 7.4, 15.8)
• Pts not refractory to bortezomib: ORR = 97%, ≥VGPR = 73%
• Patients with high BCL-2 expression vs low BCL-2 expression:
  • ORR = 94% vs 59%
  • Median Time to Progression (TTP) = 11.6 vs 5.7 months, p = 0.0044
  • Duration of Response (DOR) = 10.2 vs 7 months, p = 0.0550
• Out of 18 pts with high BCL-2 expression, 17/18 (94%) achieved at least partial response (PR) and 12/18 (66%) achieved ≥VGPR

Safety:

• Most common Adverse Events (AEs) were gastrointestinal toxicities
• Most common grade 3/4 AEs were thrombocytopenia (29%), anemia (15%) and neutropenia (14%)
• Pts discontinued the study: due to disease progression = 36, due to AEs = 5 and other reasons = 5
• Number of deaths = 5 (disease progression = 4, respiratory syncytial virus infection = 1)

Conclusion

The high rates of ORR and ≥VGPR have shown that the combination of venetoclax with bortezomib and dexamethasone could have a positive impact on RRMM therapy. The study also found that patients who were non-refractory to bortezomib had even better ORR and ≥VGPR responses. Predictably, high BCL-2 expression correlated with a much higher overall response compared to patients with low BCL-2 expression, suggesting that venetoclax could serve as a targeted therapy for pre-screened patients. The overall safety profile was found to be acceptable. Based on the efficacy and safety data, the maximum tolerated dose was determined as 800mg, and will be recommended for use in phase II trials.

 Abstract

Anti-apoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that co-targeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase Ib trial studied patients with relapsed/refractory MM receiving daily venetoclax (50–1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. Sixty-six patients were enrolled (54, dose-escalation cohorts; 12, safety expansion). Patients had received median 3 prior therapies (range: 1–13); 26 (39%) were refractory to prior bortezomib, 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea [46%], constipation [41%], nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (≥VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥VGPR 73% were seen in patients not refractory to bortezomib who had 1–3 prior therapies. Patients with high BCL2 expression had high ORR (94% [17/18]) vs patients with low BCL2 expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at https://clinicaltrials.gov/as #NCT01794507.